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Ketolides
General information
The ketolides cethromycin (ABT-773) and telithromycin are semisynthetic derivatives of 14-membered-ring macrolide antibiotics, members of the macrolide-lincosamide-streptogramin-B, MLS(B), class of antimicrobials, but they differ from macrolides by having a 3-keto group instead of an l -cladinose group on the erythronolide A ring [ ]. In a study of the efficacy of the ketolides HMR 3004 (previously RU 004) and telithromycin (HMR 3647, previously 66 647) against beta-lactamase-producing Haemophilus influenzae , the in vitro activity of both ketolides against 30 clinical isolates was comparable to that of azithromycin and superior to clarithromycin and erythromycin A [ ]. Compared with macrolides, it has increased affinity for the binding sites on domains II and V of the 50S ribosomal subunit. Furthermore, HMR 3004 and HMR 3647 were both active in a murine model of experimental pneumonia, as assessed by pulmonary clearance of beta-lactamase producing H. influenzae [ ].
Cethromycin
Cethromycin is a once-daily ketolide that originated from research by Abbott Laboratories. It is effective against Streptococcus pneumoniae , including multidrug-resistant isolates, Haemophilus influenzae , Moraxella catarrhalis , Chlamydophila pneumoniae, Mycoplasma pneumoniae , and Legionella pneumophila . There have been few studies of cethromycin so far. Data on adverse effects are limited and appear to be mainly gastrointestinal; there have been no reports of serious hepatotoxicity [ , ].
Telithromycin
Telithromycin has a good spectrum of activity against respiratory pathogens, including penicillin-resistant and erythromycin-resistant pneumococci, intracellular bacteria, and atypical bacteria. It has an absolute oral availability of 57% in young and elderly subjects [ ], and the rate and extent of absorption is unaffected by food [ ]. It penetrates rapidly into bronchopulmonary, tonsillar, sinus, and middle ear tissues/fluids, achieves high concentrations at sites of infection, and concentrates within polymorphonuclear neutrophils. In a dosage of 800 mg/day it is well tolerated across all patient populations, and adverse events, most commonly diarrhea, nausea, dizziness, and vomiting, are generally mild to moderate in intensity and seldom lead to treatment withdrawal [ ].
Drug studies
Observational studies
In an open multicenter study in 432 patients with community-acquired pneumonia given telithromycin 800 mg/day for 7 days, diarrhea was reported in 8.1% and nausea in 5.8% [ ]. Six patients discontinued treatment because of allergic reactions, abdominal pain, vomiting, vertigo, or increased alanine transaminase activity, which were considered possibly related to telithromycin. Two patients had non-significant prolongation of the QT interval.
Placebo-controlled studies
In three randomized, double blind, multicenter studies in 609 patients who took telithromycin 800 mg/day for 5 days for exacerbations of chronic bronchitis, diarrhea and nausea occurred in 6.4% and 4.8% respectively [ ]. One patient had QT c interval prolongation from 488 ms to 531 ms, which returned to baseline after the end of therapy.
Organs and systems
Cardiovascular
Telithromycin causes prolongation of the QT interval, especially in elderly patients with predisposing conditions [ ], but not in healthy men and women [ ], and a warning has been issued against using it in patients who are already at increased risk, including those receiving class IA and class III antidysrhythmic agents [ ].
Torsade de pointes has been reported [ ].
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